Objective： To analyze Fms-like tyrosine kinase 3 （FLT3）/internal-tandem duplications （ITD） mutations in various kinds of hematologic malignancy patients. Methods： FLT3/ITD gene mutations were detected by polymer...Objective： To analyze Fms-like tyrosine kinase 3 （FLT3）/internal-tandem duplications （ITD） mutations in various kinds of hematologic malignancy patients. Methods： FLT3/ITD gene mutations were detected by polymerase chain reaction （PCR） in 103 acute myeloid leukemia （AML） cases, 63 acute lymphocytic leukemia （ALL） cases, 53 chronic myelogenous leukemia （CML） cases in chronic phase （CML-CP）, 34 CML cases in blast crisis （CML-BC）, 11 chronic lymphatic leukemia （CLL） cases, 36 myelodysplastic syndrome （MDS） cases, 9 multiple myeloma （MM） cases and 13 non-hodgkin＇s lymphoma （NHL） cases with marrow infiltration. Results： The expressions of FLT3/ITD gene mutations were detected in 22.3% AML cases, in 6.5% CML-BC cases, in 5.6% MDS cases and in 2.6% ALL cases. The two ALL cases with FLT3/ITD mutation were diagnosed as ALL-L2 with morphology and both with myeloid antigen expression, but finally were diagnosed as acute mixed-lineage leukemia after immunology examination. FLT3/ITD gene mutations were not detected in CML-CP, MM, NHL and CLL cases. In the 23 AML patients with FLT3/ITD gene mutation, including 2 of 8 M1 （2.5%）, 8 of 33 M2 （24.2%）, 7 of 24 M3 （29.3%）, 2 of 11 M4 （18.2%）, 3 of 21 M5 （14.3%）, 1 of 5 M6 （20%）, and 0 of 1 M7 cases, and there were no significant differences in the positive rates of FLT3/ITD mutations between the FAB subtypes （P 〉 0.05）. Statistical analyses showed that in AML patients, FLT3/ITD was associated with a higher peripheral blood white cell （WBC） counts [（41.23 ± 32.56） x 109/L vs （11.36 ± 9.89） × 10^9/L （P 〈 0.01 ）], higher percentage of bone marrow blast cells [（72.78 ± 21.79）% vs （51.26 ± 20.78）% （P 〈 0.05）], and higher cumulative relapse rates （63.6% vs 27.7%, P 〈 0.025） than those negative. Conclusion： FLT3/ITD gene mutation mainly occurred in AML patients, and might be a strong prognostic factor which was associated with high peripheral WBC counts, bone marrow blast cell proportion and a increased relapse risk in AML. Detection of FLT3/ITD gene mutation might provide insights to explore a more accurate genotyping of leukemia, differential diagnosis between AML and ALL, subdivide risk level in AML and estimate prognosis of leukemia.展开更多
BACKGROUND Congenital lymphangiectasia is a rare disease characterized by dilated interstitial lymphatic vessels and cystic expansion of the lymphatic vessels.Congenital lymphangiectasia can affect various organ syste...BACKGROUND Congenital lymphangiectasia is a rare disease characterized by dilated interstitial lymphatic vessels and cystic expansion of the lymphatic vessels.Congenital lymphangiectasia can affect various organ systems;however,it frequently occurs in the lungs accompanied with unexplained pleural effusion.Further,it might not be diagnosed during prenatal examination owing to the absence of pronounced abnormalities.However,after birth the newborn rapidly develops respiratory distress that quickly deteriorates.Genetic variations in proteins controlling the development of lymphatic vessels contribute to the pathophysiology of this disease.We report a rare case of heterozygous mutation of ADAMTS3 and FLT4 genes,which have not been reported previously.CASE SUMMARY We analysed the case of a neonate who had presented with only pleural effusion at a late gestational age and eventually died due to its inability to establish spontaneous breathing after birth.An autopsy revealed lymphangiectasia of the organ systems.Further,whole exome sequencing revealed heterozygous mutations of the lymphangiogenesis-controlling genes,ADAMTS3 and FLT4,and Sanger verification revealed similar lesions in the mother with no symptoms.CONCLUSION Considering the presented case,obstetricians should observe unexplained foetal pleural effusion,and perform pathology analysis and whole exome sequencing for a conclusive diagnosis and prompt treatment.展开更多
Summary： Patients with FLT3-ITD^mmutt/NPM1- cytogenetically normal acute myeloid leukemia （CN-AML）, as high-risk molecular group in CN-AML, are associated with a worse prognosis than other CN-AML patients. It is be...Summary： Patients with FLT3-ITD^mmutt/NPM1- cytogenetically normal acute myeloid leukemia （CN-AML）, as high-risk molecular group in CN-AML, are associated with a worse prognosis than other CN-AML patients. It is beneficial to generate xenotransplantation model of FLT3-ITD^mut/NPM1- CN-AML to better understand the pathogenesis and therapeutic strategies of such AML subtype. The purpose of present study was to establish the xenotransplantation model in NOD/SCID mice with FLT3-ITD^mut/NPM1- CN-AML primary cells. The FLT3-ITD^mut/NPM1- CN-AML primary cells from 3 of 7 cases were successfully transplanted into NOD/SCID mice, and human CD45 positive cells were detected in the peripheral blood, spleen and bone marrow of mice by using flow cytometry. Infiltration of human leukemia cells in various organs of mice was observed by using immunohistochemistry. Gene analysis confirmed sustained FLT3/ITD mutation without NPM1 mutation in mice. By performing serial transplantation, it was found that characteristics of the leukemia cells in secondary and tertiary genera- tion models remained unchanged. Moreover, in vivo cytarabine administration could extend survival of NOD/SCID mice, which was consistent with clinical observation. In conclusion, we successfully estab- lished xenotransplantation model of human FLT3-ITD^mut/NPM1- CN-AML in NOD/SCID mice. The model was able to present primary disease and suitable to evaluate the curative effects of new drugs or therapy strategies.展开更多
Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic i...Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic impact of the two gene mutations in Chinese AML patients, we used multiplex polymerase chain reaction （PCR） and capillary electrophoresis to screen 76 AML patients with normal cytogenetics for mutations in FLT3 internal tandem duplication （FLT3/ITD） and exon 12 of the NPM1 gene. FLT3/ITD mutation was detected in 15 （19.7%） of 76 subjects, and NPM1 mutation in 20 （26.3%） subjects. Seven （9.2%） cases were positive for both FLT3/ITD and NPM1 mutations Significantly more FLT3/ITD aberration was detected in subjects with French-American-British （FAB） M1 （42.8%）. NPM1 mutation was frequently detected in subjects with M5 （47.1%） and infrequently in subjects with M2 （11.1%）. FLT3 and NPM1 mutations were significantly associated with a higher white blood cell count in peripheral blood and a lower CD34 antigen expression, but not age, sex, or platelet count. Statistical analysis revealed that the FLT3/ITD- positive group had a lower complete remission （CR） rate （53.3% vs. 83.6%）. Survival analysis showed that the FLT3/ITD-positive/NPM1 mutation-negative group had worse overall survival （OS） and relapse-free survival （RFS）. The FLT3/ITD-positive/NPM1 mutation-positive group showed a trend towards favorable survival compared with the FLT3/ITD-positive/NPM1 mutation-negative group （P=0.069）. Our results indicate that the FLT3/ITD mutation might be a prognostic factor for an unfavorable outcome in Chinese AML subjects with normal cytogenetics, while NPM1 mutation may be a favorable prognostic factor for OS and RFS in the presence of FLT3/ITD.展开更多
文摘Objective： To analyze Fms-like tyrosine kinase 3 （FLT3）/internal-tandem duplications （ITD） mutations in various kinds of hematologic malignancy patients. Methods： FLT3/ITD gene mutations were detected by polymerase chain reaction （PCR） in 103 acute myeloid leukemia （AML） cases, 63 acute lymphocytic leukemia （ALL） cases, 53 chronic myelogenous leukemia （CML） cases in chronic phase （CML-CP）, 34 CML cases in blast crisis （CML-BC）, 11 chronic lymphatic leukemia （CLL） cases, 36 myelodysplastic syndrome （MDS） cases, 9 multiple myeloma （MM） cases and 13 non-hodgkin＇s lymphoma （NHL） cases with marrow infiltration. Results： The expressions of FLT3/ITD gene mutations were detected in 22.3% AML cases, in 6.5% CML-BC cases, in 5.6% MDS cases and in 2.6% ALL cases. The two ALL cases with FLT3/ITD mutation were diagnosed as ALL-L2 with morphology and both with myeloid antigen expression, but finally were diagnosed as acute mixed-lineage leukemia after immunology examination. FLT3/ITD gene mutations were not detected in CML-CP, MM, NHL and CLL cases. In the 23 AML patients with FLT3/ITD gene mutation, including 2 of 8 M1 （2.5%）, 8 of 33 M2 （24.2%）, 7 of 24 M3 （29.3%）, 2 of 11 M4 （18.2%）, 3 of 21 M5 （14.3%）, 1 of 5 M6 （20%）, and 0 of 1 M7 cases, and there were no significant differences in the positive rates of FLT3/ITD mutations between the FAB subtypes （P 〉 0.05）. Statistical analyses showed that in AML patients, FLT3/ITD was associated with a higher peripheral blood white cell （WBC） counts [（41.23 ± 32.56） x 109/L vs （11.36 ± 9.89） × 10^9/L （P 〈 0.01 ）], higher percentage of bone marrow blast cells [（72.78 ± 21.79）% vs （51.26 ± 20.78）% （P 〈 0.05）], and higher cumulative relapse rates （63.6% vs 27.7%, P 〈 0.025） than those negative. Conclusion： FLT3/ITD gene mutation mainly occurred in AML patients, and might be a strong prognostic factor which was associated with high peripheral WBC counts, bone marrow blast cell proportion and a increased relapse risk in AML. Detection of FLT3/ITD gene mutation might provide insights to explore a more accurate genotyping of leukemia, differential diagnosis between AML and ALL, subdivide risk level in AML and estimate prognosis of leukemia.
基金The Wu Jieping Medical Foundation Clinical Research Special Grant Fund in China,No.320.6750.2022-15-9.
文摘BACKGROUND Congenital lymphangiectasia is a rare disease characterized by dilated interstitial lymphatic vessels and cystic expansion of the lymphatic vessels.Congenital lymphangiectasia can affect various organ systems;however,it frequently occurs in the lungs accompanied with unexplained pleural effusion.Further,it might not be diagnosed during prenatal examination owing to the absence of pronounced abnormalities.However,after birth the newborn rapidly develops respiratory distress that quickly deteriorates.Genetic variations in proteins controlling the development of lymphatic vessels contribute to the pathophysiology of this disease.We report a rare case of heterozygous mutation of ADAMTS3 and FLT4 genes,which have not been reported previously.CASE SUMMARY We analysed the case of a neonate who had presented with only pleural effusion at a late gestational age and eventually died due to its inability to establish spontaneous breathing after birth.An autopsy revealed lymphangiectasia of the organ systems.Further,whole exome sequencing revealed heterozygous mutations of the lymphangiogenesis-controlling genes,ADAMTS3 and FLT4,and Sanger verification revealed similar lesions in the mother with no symptoms.CONCLUSION Considering the presented case,obstetricians should observe unexplained foetal pleural effusion,and perform pathology analysis and whole exome sequencing for a conclusive diagnosis and prompt treatment.
基金supported by the National Natural Science Foundation of China (No. 81200380)
文摘Summary： Patients with FLT3-ITD^mmutt/NPM1- cytogenetically normal acute myeloid leukemia （CN-AML）, as high-risk molecular group in CN-AML, are associated with a worse prognosis than other CN-AML patients. It is beneficial to generate xenotransplantation model of FLT3-ITD^mut/NPM1- CN-AML to better understand the pathogenesis and therapeutic strategies of such AML subtype. The purpose of present study was to establish the xenotransplantation model in NOD/SCID mice with FLT3-ITD^mut/NPM1- CN-AML primary cells. The FLT3-ITD^mut/NPM1- CN-AML primary cells from 3 of 7 cases were successfully transplanted into NOD/SCID mice, and human CD45 positive cells were detected in the peripheral blood, spleen and bone marrow of mice by using flow cytometry. Infiltration of human leukemia cells in various organs of mice was observed by using immunohistochemistry. Gene analysis confirmed sustained FLT3/ITD mutation without NPM1 mutation in mice. By performing serial transplantation, it was found that characteristics of the leukemia cells in secondary and tertiary genera- tion models remained unchanged. Moreover, in vivo cytarabine administration could extend survival of NOD/SCID mice, which was consistent with clinical observation. In conclusion, we successfully estab- lished xenotransplantation model of human FLT3-ITD^mut/NPM1- CN-AML in NOD/SCID mice. The model was able to present primary disease and suitable to evaluate the curative effects of new drugs or therapy strategies.
文摘Mutations of fins-like tyrosine kinase 3 （FLT3） and nucleophosmin （NPM1） exon 12 genes are the most common abnormalities in adult acute myeloid leukemia （AML） with normal cytogenetics. To assess the prognostic impact of the two gene mutations in Chinese AML patients, we used multiplex polymerase chain reaction （PCR） and capillary electrophoresis to screen 76 AML patients with normal cytogenetics for mutations in FLT3 internal tandem duplication （FLT3/ITD） and exon 12 of the NPM1 gene. FLT3/ITD mutation was detected in 15 （19.7%） of 76 subjects, and NPM1 mutation in 20 （26.3%） subjects. Seven （9.2%） cases were positive for both FLT3/ITD and NPM1 mutations Significantly more FLT3/ITD aberration was detected in subjects with French-American-British （FAB） M1 （42.8%）. NPM1 mutation was frequently detected in subjects with M5 （47.1%） and infrequently in subjects with M2 （11.1%）. FLT3 and NPM1 mutations were significantly associated with a higher white blood cell count in peripheral blood and a lower CD34 antigen expression, but not age, sex, or platelet count. Statistical analysis revealed that the FLT3/ITD- positive group had a lower complete remission （CR） rate （53.3% vs. 83.6%）. Survival analysis showed that the FLT3/ITD-positive/NPM1 mutation-negative group had worse overall survival （OS） and relapse-free survival （RFS）. The FLT3/ITD-positive/NPM1 mutation-positive group showed a trend towards favorable survival compared with the FLT3/ITD-positive/NPM1 mutation-negative group （P=0.069）. Our results indicate that the FLT3/ITD mutation might be a prognostic factor for an unfavorable outcome in Chinese AML subjects with normal cytogenetics, while NPM1 mutation may be a favorable prognostic factor for OS and RFS in the presence of FLT3/ITD.
